Certain 1-substituted aminomethyl imidazole and pyrrole derivatives: novel dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula: ##STR1## wherein: A represents arylalkyl, aryl or heteroaryl; X is nitrogen or CH; and R 2 , R 3 , R 4  and R 5  represent organic or inorganic substituents; 
     and the pharmaceutically acceptable salts thereof; 
     useful for treating disorders of the central nervous system.

This is a continuation application of U.S. Ser. No. 08/344,498, filedNov. 23, 1994 now U.S. Pat. No. 5,478,934.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain 1-substituted aminomethylimidazole andpyrrole derivatives which selectively bind to brain dopamine receptorsubtypes. This invention also relates to pharmaceutical compositionscomprising such compounds. It further relates to the use of suchcompounds in treating affective disorders such as schizophrenia anddepression as well as certain movement disorders such as Parkinsonism.

2. Description of the Related Art

Schizophrenia or psychosis is a term used to describe a group ofillnesses of unknown origin which affect approximately 2.5 millionpeople in the United States. These disorders of the brain arecharacterized by a variety of symptoms which are classified as positive(disordered thought, hallucinations and delusions) and negative symptoms(social withdrawal and unresponsiveness). These disorders have an ageonset of adolescence or early adulthood and persist for many years. Thedisorders tend to become more severe during the patient's lifetime andcan result in prolonged institutionalization. In the U.S. today,approximately 40% of all hospitalized psychiatric patients suffer fromschizophrenia.

During the 1950's physicians demonstrated that they could successfullytreat psychotic patients with medications called neuroleptics; thisclassification of antipsychotic medication was based largely on theactivating (neuroleptic) properties of the nervous system by thesedrugs. Subsequently, neuroleptic agents were shown to increase theconcentrations of dopamine metabolites in the brain suggesting alteredneuronal firing of the dopamine system. Additional evidence indicatedthat dopamine could increase the activity of adenylate cyclase in thecorpus striatum, an effect reversed by neuroleptic agents. Thus,cumulative evidence from these and later experiments strongly suggestedthat the neurotransmitter dopamine was involved in schizophrenia.

One of the major actions of antipsychotic medication is the blockade ofdopamine receptors in the brain. Several dopamine systems appear toexist in the brain and at least five classes of dopamine receptorsappear to mediate the actions of this transmitter. These dopaminereceptors differ in their pharmacological specificity and wereoriginally classified upon these differences in the pharmacology ofdifferent chemical series. Butyrophenones, containing many potentantipsychotic drugs were quite weak at the dopamine receptor thatactivated adenylate cyclase (now known as the D1 dopamine receptor). Incontrast, they labeled other dopamine receptors (called D2 receptors) inthe subnanomolar range and a third type D3 in the nanomolar range. Twoadditional receptor subtypes have also been identified. D5 which issomewhat similar to D1 receptor type and D4 which is closely related toD3 and D2 receptor types. Phenothiazines possess nanomolar affinity forall three types of dopamine receptors. Other drugs have been developedwith great specificity for the D1 subtype receptor and for the D2subtype receptor.

Recently a new group of drugs (such as sulpiride and clozapine) havebeen developed with a lesser incidence of extrapyramidal side effectsthan classical neuroleptics. In addition, there is some indication thatthey may be more beneficial in treating negative symptoms in somepatients. Since all D2 blockers do not possess a similar profile,hypotheses underlying the differences have been investigated. The majordifferences have been in the anticholinergic actions of the neurolepticsas well as the possibility that the dopamine receptors may differ inmotor areas from those in the limbic areas thought to mediate theantipsychotic responses. The existence of the D3, D4, (Van Tol, et al,Nature (London) 1991, 350, 610) D5 (Sunahara, et al, Nature (London)1991, 350, 614) and other as yet undiscovered dopamine receptors maycontribute to this profile. Some of the atypical compounds possesssimilar activity at both D2, D3 and D4 receptors. The examples of thispatent fall into this general class of molecules.

Using molecular biological techniques it has been possible to clonecDNA's coding for each of the pharmacologically defined receptors. Thereare at least two forms of D1 which have been identified as D1 and D5,and two forms of D2, identified now as D2 and D4 dopamine receptors. Inaddition, there is at least one form of D3 dopamine receptor. Examplesfrom the aminomethyl phenylimidazole series of this patent possessdifferential affinities for each receptor subtype.

German Patent Application DE. 3627155 describes the preparation of1-aryimidazole-4-carboxamide derivatives.

The synthesis of a series of N-aryl pyrroles including 1 phenyl,2,5-dimethyl-4-(4-methylpiperazine-1-ylmethyl)pyrroles and theirantimicrobial activity has been described by F. Cerreto, M. Scalzo, AVillar in Farmaco (1993) 48(12) 1735-46 and Euro J. Med. Chem. (1992)27(7), 701-8.

U.S. Pat. No. 5,159,083 discloses 4-Aminoalkyl 2-phenylimidazoles. U.S.Pat. No. 4,829,065 describes a series of 1-(Diphenylmethyl)-4- (5methyl-2-p-tolylimidazol-4-yl)methyl!piperazines. European PatentApplication 87200296.9 discloses 2-Aryl-5(N-piperazinyl)methyl pyrroles.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine receptor subtypes.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in treatingaffective disorders such as schizophrenia and depression as well ascertain movement disorders such as Parkinsonism. Furthermore compoundsof this invention may be useful in treating the extrapyramidyl sideeffects associated with the use of conventional neuroleptic agents.Since particularly D3 and D4 receptor subtypes are concentrated in thelimbic system (Taubes, Science, 1994, 265, 1034) which controlscognition and emotion, compounds which interact with these receptorsalso have utility in the treatment of cognitive disorders. Suchdisorders include cognitive deficits which are a significant componentof the negative symptoms (social withdrawal and unresponsiveness) ofschizophrenia. Other disorders involving memory impairment and attentiondeficit disorders may also be treated with the compounds of thisinvention that interact specifically with D3 and D4 receptors.Accordingly, broad embodiments of the invention is directed to compoundsof Formulas I and II: ##STR2## wherein: A is arylalkyl, aryl orheteroaryl optionally substituted with up to 3 groups selected from thegroup consisting of halogen trifluoromethyl, hydroxy, straight orbranched chain lower alkyl having 1-6 carbon atoms or straight orbranched chain lower alkoxy having 1-6 carbon atoms.

X is N or CR₁ where R₁ may be hydrogen, halogen straight or branchedchain lower alkyl having 1-6 carbon atoms or phenyl substituted orunsubstituted.

R₂ is hydrogen, straight or branched chain, lower alkyl having 1-6carbon atoms or phenyl substituted or unsubstituted;

R₃ is hydrogen or straight or branched chain lower alkyl having 1-6carbon atoms, or R₃ and R₄ together may represent --(CH₂)n₂ -- where n₂is 3 or 4; and

R₄ and R₅ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, aryl straight orbranched chain lower alkyl having 1-6 carbon atoms; or

NR₄ R₅ together represent 2-(1,2,3,4-tetrahydroisoquinolinyl), eitherunsubstituted or mono or disubstituted with halogen, hydroxy, straightor branched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms or;

NR₄ R₅ represents ##STR3## where W is N or CH;

R₇ is hydrogen, arylalkyl, particularly benzyl, benzoyl, phenyl, pyridylor pyrimidinyl, unsubstituted or mono or disubstituted with halogen,hydroxy, straight or branched chain lower alkyl having 1-6 carbon atoms,or straight or branched chain lower alkoxy having 1-6 carbon atoms; and

n is 1, 2, or 3 when W is CH, or n is 2 or 3 when W is N; or NR₄ R₅represents ##STR4## where R₇ is as defined above.

Alternatively, in Formula I, R₂ and A, where A is phenyl, may togetherform a tricyclic structure fused to the 5-membered nitrogen heterocycleto yield tetracyclic compounds of formula ##STR5## where Y is oxygen,--OCH₂ --, sulfur, --SCH₂ --, or NR or --NRCH₂ -- where R representshydrogen or alkyl; or

Y is --CH=CH-- or --(CH₂)m -- where m=0, 1, 2; and

X, R₃, R₄, and R₅ are as defined above.

The interaction of the 1-substituted aminomethylimidazole and pyrrolederivatives of the invention with dopamine receptor subtypes results inthe pharmacological activities of these compounds. These compounds arehighly selective partial agonists or antagonists at brain dopaminereceptor subtypes or prodrugs thereof and are useful in the diagnosisand treatment of affective disorders such as schizophrenia anddepression as well as certain movement disorders such as Parkinsonism.Furthermore, compounds of this invention are useful in treating theextrapyramidyl side effects associated with the use of conventionalneuroleptic agents.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-1E show representative aminomethyl phenylimidazoles of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can berepresented by general formulas I and II shown above.

Preferred compound of Formula I include those where A is phenyl,pyridyl, or naphthyl.

The present invention further encompasses compounds from Formula III:##STR6## where Z is hydrogen, halogen, trifluoromethyl, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, orstraight or branched chain lower alkoxy having 1-6 carbon atoms;

T is hydrogen, halogen, hydroxy, straight or branched chain lower alkylhaving 1-6 carbon atoms, straight or branched chain lower alkoxy having1-6 carbon atoms; and

X, R₃, R4 and R₅ are as defined above for Formula I.

Alternatively, Z and T may form an additional ring as indicated byFormula IV and V ##STR7## where n=1-3; and X, R₃, R4 and R5 are asdefined above for Formula I.

The present invention also encompasses compounds or Formula VI ##STR8##where Z is hydrogen, halogen, trifluoromethyl, straight or branchedchain lower alkyl having 1-6 carbon atoms or straight or branched chainlower alkoxy having 1-6 carbon atoms; and

X, R₃, R₄ and R₅ are as defined above for Formula I.

The invention further provides compounds of Formula VII ##STR9## where Zand T are as defined above for Formula I; and W represents phenyl orphenylalkyl where the phenyl group is optionally mono- or disubstitutedwith halogen, alkyl, or alkoxy.

Preferred compounds of Formula VII are those where Z and T are hydrogenand W represents phenyl or benzyl.

The invention further provides compounds of Formula VIII ##STR10## whereZ and T are as defined above for Formula I; and W represents phenyl,pyrimidinyl, pyridyl, or phenylalkyl where the phenyl group isoptionally mono- or disubstituted with halogen, alkyl, or alkoxy.

Preferred compounds of Formula VIII are those where Z and T are hydrogenand W represents phenyl, pyrimidinyl, pyridyl, or benzyl.

The invention further provides compounds of Formula IX ##STR11## where Zand T are as defined above for Formula I; V is nitrogen or CH; and Wrepresents phenyl, pyrimidinyl, pyridyl, or phenylalkyl where the phenylgroup is optionally mono- or disubstituted with halogen, alkyl, oralkoxy.

Preferred compounds of Formula IX are those where Z and T are hydrogen,V is CH; and W represents phenyl or benzyl. Other preferred compounds ofFormula IX are those where Z and T are hydrogen, V is nitrogen and Wrepresents phenyl, pyrimidinyl, pyridyl, or benzyl.

The invention also provides compounds of Formula X ##STR12## where Wrepresents phenyl or phenylalkyl where the phenyl group is optionallymono- or disubstituted with halogen, alkyl, or alkoxy.

Preferred compounds of Formula X are those where W is phenyl or benzyl.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. 1and their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic,hydroiodic, acetic and the like. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By aryl or "Ar" is meant an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed rings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), whichcan optionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By alkyl and lower alkyl is meant straight and branched chain alkylgroups having from 1-6 carbon atoms.

By lower alkoxy and alkoxy is meant straight and branched chain alkoxygroups having from 1-6 carbon atoms.

By heteroaryl is meant 5, 6, or 7 membered aromatic ring systems havingat least one hetero atom selected from the group consisting of nitrogen,oxygen and sulfur. Examples of heteroaryl groups are pyridyl,pyrimidinyl, pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl,furanyl, quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By halogen is meant fluorine, chlorine, bromine and iodine.

By arylalkyl and aralkyl is meant the group --R-Ar where Ar is an arylgroup and R is a straight or branched chain aliphatic group. Arylalkylgroups may optionally be substituted with, e.g., halogen, lower alkyllower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy, andhydroxy. Preferred arylalkyl groups in the above formulas where W is CHand R₈ represents arylalkyl are phenylalkyl groups where the alkylportion is lower alkyl. A particularly preferred phenylalkyl group isbenzyl where the phenyl ring may be substituted with up to threesubstituents independently selected from hydrogen, halogen,trifluoromethyl, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, or straight or branched chain lower alkoxy having 1-6carbon atoms.

By cycloalkyl is meant cyclic hydrocarbons having from 3-8 carbon atoms.These cyclic hydrocarbon groups may be substituted with up to threesubstituents independently selected from hydrogen, halogen,trifluoromethyl, cyano, straight or branched chain lower alkyl having1-6 carbon atoms, hydroxy, straight or branched chain lower alkyl having1-6 carbon atoms, straight or branched chain lower alkoxy having 1-6carbon atoms, or SO₂ R₉ where R₉ is NH₂ or NHCH₃.

The pharmaceutical utility of compounds of this invention are indicatedby the following assays for dopamine receptor subtype affinity.

Assay for D2 and D3 Receptor Binding Activity

Striatial tissue is dissected from adult male Sprague Dawley rats or BHK293 cells are harvested containing recombinantly produced D2 or D3receptors. The sample is homogenized in 100 volumes (w/vol) of 0.05MTris HCl buffer at 4° C. and pH 7.4. The sample is then centrifuged at30,000×g and resuspended and rehomogenized. The sample is thencentrifuged as described and the final tissue sample is frozen untiluse. The tissue is resuspended 1:20 (wt/vol) in 0.05M Tris HCl buffercontaining 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.5 ml of tissuesample, 0.5 nM 3H-raclopride and the compound of interest in a totalincubation of 1.0 ml. Nonspecific binding is defined as that bindingfound in the presence of 10-4M dopamine; without further additions,nonspecific binding is less than 20% of total binding. The bindingcharacteristics of examples of this patent are shown in Table 1 for RatStriatal Homogenates.

                  TABLE I                                                         ______________________________________                                        Compound Number.sup.1                                                                         IC.sub.50 (μM)                                             ______________________________________                                        1               0.142                                                         2               0.003                                                         3               0.006                                                         6               0.194                                                         ______________________________________                                         .sup.1 Compound numbers relate to compounds shown in FIG. I.             

Assay for D4 Receptor Binding Activity

Clonal cell lines expressing the human dopamine D4 receptor subtype wereharvested in PBS and the cells centrifuged and the pellets stored at-80° C. until used in the binding assay. The pellets were resuspendedand the cells lysed at 4° C. in 50 mM Tris pH 7.4 buffer containing 120mM NaCl, 2 mM EDTA and 5 mM mMgCl₂. The homogenate is centrifuged at48000×g for 10 minutes at 4° C. The resulting pellet is resuspended infresh buffer and centrifuged again. After resuspension of the pellet infresh buffer at 100 ul aliquot removed for the protein determination.The remaining homogenate is centrifuged as above, the supernatantremoved and the pellet stored at 4° C. until needed at which time it isresuspended to a final concentration of 625 ug/ml (250 ug per sample)with 50 mM Tris buffer (pH 7.4) and 120 mM NaCl just prior to use.Incubations were carried out for 60 minutes at 25° C. in the presence of0.1 nM ³ H! YM-09151-2. The incubation was terminated by rapidfiltration through Whatman GF/C filters and rinsed with 2×4 ml washes ofchilled 50 mM Tris (pH 7.4) and 120 mM NaCl. Nonspecific binding wasdetermined with 1 uM spiperone and radioactivity determined by countingin an LKB beta counter. Binding parameters were determined by non-linearleast squares regression analysis, from which the inhibition constant Kicould be calculated for each test compound. The binding characteristicsof some examples of this patent are shown in Table 2 for the dopamine D4binding assay. In general, compounds of the accompanying examples weretested in the above assay, and all were found to possess a Ki value forthe displacement of ³ H! YM-09151-2 from the human dopamine D4 receptorsubtype of below 500 mM. Some specific data is indicated in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound Number.sup.1                                                                          Ki(μM)                                                    ______________________________________                                        1                0.003                                                        2                0.010                                                        3                0.002                                                        6                0.003                                                        ______________________________________                                    

Compounds 1, 3, and 6 are particularly preferred embodiments of thepresent invention because of their potency in binding to dopaminereceptor subtypes.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjutants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjutants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsion, hard or soft capsules or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumsterate, stearic acid or talc. the tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl disterate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample calcium carbonate, calcium posphate of kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents may be a naturally occurring phosphatide, for example,lecithin, or condensation products of an alkylene oxide with fattyacids, for example polyoxyethylene sterate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring gums, for example gum acacia or gum tragacanth,naturally occurring phospatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycol, sorbitol or sucrose. Such formulations may also containa demulcent, a preservative and flavoring and coloring agents. Thepharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspensions. This suspension may be formulatedaccording to known art using those suitable dispersing or wetting agentsand suspending agents which have been mentioned above. The sterileinjectable preparation may also be sterile injectable solution orsuspension in a non-toxic parentally acceptable diluent or solvent, forexample as a solution of 1,3-butanediol. Among the acceptable vehiclesand solvents that may be employed are water, Ringer's solution andisotonic sodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjutants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a singe dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between ca 1 mg to about 500 mg of anactive ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of compounds if the present inventionis given in Schemes I, II and III. Those having skill in the art willrecognize that the starting materials may be varied and additional stepsemployed to produce compounds encompassed by the present invention.##STR13## where n=0, 1 or 2; Z is hydrogen, halogen, hydroxy,trifluoromethyl, straight or branched chain lower alkyl having 1-6carbon atoms or straight or branched chain lower alkoxy having 1-6carbon atoms;

T is hydrogen, halogen, hydroxy, straight or branched chain lower alkylhaving 1-6 carbon atoms or straight or branched chain lower alkoxyhaving 1-6 carbon atoms; or

Z and T may together form an carbocyclic or heterocyclic ring system;and

R₄ and R₅ are as defined as above for Formula I.

Representative illustrations of the starting materials A have beendescribed by Antonini et al., Euro. J. Med. Chem., 19:285 (1984).##STR14## where all the substituents are as defined above.

Representative illustrations of the starting materials B are describedin the literature. See, e.g., J. Wasley and K. Chan, Synth. Commun., 3(4): 303-4 (1973). ##STR15## where all the substituents are as definedpreviously.

Representative illustrations of the starting materials C have beendescribed by M. Gall and B. Kaundar, J. Org. Chem., 46:1575 (1981).

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described in them.

EXAMPLE I ##STR16##

A solution of 50 mg of 4-hydroxymethyl-1-phenyl imidazole in 1 mL ofthionyl chloride was heated at 60° C. for 1 hr. The excess thionylchloride was removed by evaporation under reduced pressure. The residuewas dissolved in 5 mL of chloroform and a mixture of 50 mg 4benzylpiperidine and 0.5 mL N-ethyl-N,N diisopropylamine added. Thereaction mixture was heated at 60° C. for 6 hr and then allowed to coolto room temperature. The reaction mixture then washed successively with5 ml aliquots of 1N, NaOH and brine. The organic extracts were driedover anhydrous sodium sulfate and the solvent evaporated under reducedpressure to yield 1-phenyl-4 (4-benzyl-piperidin-1-yl)-methyl!imidazole,which after purification by chromatography on silica gel using 5%methanol in methylene chloride as elvent was converted to itsdihydrochloride salt using ether/HCl. 1-phenyl-4-benzyl-piperidin-1-y)methyl!imidazole dihydrochloride salt had a m.p. of245°-8° C.

EXAMPLE II

The following compounds were prepared essentially according to theprocedures described in Example I:

a) 1-Phenyl-4 (4-phenyl-piperidin-1-yl)methyl!imidazole dihydrochloride(compound 2) melting at 230°-233° C.

b) 1-Phenyl-4 (4-phenyl-piperazin-1-yl)methyl!imidazole dihydrochloride(compound 3) melting at 233°-237° C.

c) 1-Phenyl-4 (4-fluorobenzyl-piperidin-1-yl)methyl! imidazoledihydrochloride (compound 4) melting at 238°-241° C.

d) 1-Phenyl-4 (4-(4-fluoropyrimidin-2-yl)piperazin-1-yl)methyl!imidazoledihydrochloride (compound 5) melting at 233°-5° C.

e) 1-Phenyl-4 (4-(4-fluorophenyl)-piperazin-1-yl)methyl!imidazoledihydrochloride (compound 6) melting at 245°-7° C.

EXAMPLE III ##STR17##

A mixture of 931 mg aniline and 2.0 g of 2,5-dimethoxytetrahydrofuran-3-carboxaldehyde in 10 mL of acetic acid was heated at90° C. for 2 hr. The acetic acid was removed by evaporation underreduced pressure and the residue was extracted into 50 mL of ethylacetate. The organic extract was washed successively with 50 ml of 10%sodium bicarbonate and water, dried over anhydrous sodium sulfate andthe solvent evaporated under reduced pressure to yield 1 g of 1 phenylpyrrole-3-carboxaldehyde as a yellow oil which was used in the next stepwithout further purification or characterization.

To a solution of 171 mg of 1-phenyl pyrrole-3-carboxaldehyde in 1 mL ofmethanol was added 525 mg of 4-benzylpiperidine, 175 mg of4-benzylpiperidine·HCl and 63 mg of sodium cyanoborohydride. Thereaction mixture was stirred overnight at room temperature under anatmosphere of nitrogen. The methanol was removed by evaporation underreduced pressure and the residue was extracted into 50 mL of ethylacetate, then washed successively with 50 mL aliquots of 10% sodiumhydroxide and water. The ethyl acetate extract was dried over anhydroussodium sulfate and the solvent evaporated under reduced pressure toyield 1-phenyl-3 (4-benzyl-piperidin-1-yl)methyl!pyrrole, which waspurified by chromatography on silica gel using 5% methanol indichloromethane as elvent. On evaporation of the solvent, the free basewas dissolved in ethanol and treated with 1 equivalent of maleic acid.The 1-phenyl-3 (4-benzyl-piperidin-1-yl)methyl!pyrrole maleate salt(compound 7) had a melting point of 159°-161° C.

EXAMPLE IV ##STR18##

A mixture of 4 g of 10,11 dihydrobenz b,f! 1,4!oxazepin-11-thione and 4g of 2-amino-1,1,dimethoxy propane in 40 mL of 1-butanol was heated atreflux temperature for 2 days. The solvent was then removed byevaporation under reduced pressure and the residue was dissolved in 10mL conc. sulfuric acid and stirred at room temperature for 30 min. Thereaction mixture was poured into 250 mL ice-water. The aqueous mixturewas then basified with 3N sodium hydroxide and extracted with 2×100 mLof ethyl acetate. The combined organic extracts were washed with 2×100mL brine, dried over anhydrous sodium sulfate and the solvent removed byevaporation under reduced pressure to yield 100 mg of2-methyl-9H-dibenzo b,f!imidazo 1,2d! 1,4!oxazepine. This material wasused in the next step without further purification or characterization.

To a suspension of 35 mg of 2-methyl-9H-dibenzo b,f!imidazo 1,2d!1,4!oxazepine in 3 mL of carbon tetrachloride was added 20 mg of1,3-dibromo-5,5-dimethylhydantoin. The reaction mixture was stirred andirradiated with a 500 w lamp under an atmosphere of nitrogen. After 30minutes, 100 mg of 4-benzyl-piperidine and 0.5 mL triethylamine wasadded to the mixture. The reaction mixture was stirred for 4 hr. at roomtemperature and then washed with 1N sodium hydroxide solution. Theorganic layer was dried over anhydrous sodium sulfate, and the solventremoved by evaporation under reduced pressure to yield 2(4-benzyl-piperidin-1-yl)methyl-9H-dibenzo b,f!imidazo 1,2!1,4!oxazepine. This material was purified by chromatography on silicagel using 5% methanol in dichlormethane as elvent and was treated withether/HCl to yield 2 (4-benzyl-piperidin-1-yl)methyl!-9H-dibenzob,f!imidazo 1,2d 1,4!oxazepine dihydrochloride (compound 8) melting at187°-190° C.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention and the manner and process of making and using it are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude the specification.

What is claimed is:
 1. A compound of the formula ##STR19## or thepharmaceutically acceptable salts thereof wherein: A is arylalkyl, aryl,or heteroaryl optionally substituted with up to 3 groups selected fromthe group consisting of halogen, trifluoromethyl, hydroxy, straight orbranched chain lower alkyl having 1-6 carbon atoms, or straight orbranched chain lower alkoxy having 1-6 carbon atoms;X is CR₁ where R₁ ishydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms or phenyl; R₂ is hydrogen, straight or branched chain loweralkyl having 1-6 carbon atoms or phenyl; R₃ is hydrogen or straight orbranched chain lower alkyl having 1-6 carbon atoms; and NR₄ R₅ togetherrepresent 2-(1,2,3,4-tetrahydroisoquinolinyl), optionally mono- ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, or straight or branched chain loweralkoxy having 1-6 carbon atoms.
 2. A compound of the formula ##STR20##or the pharmaceutically acceptable salts thereof wherein: A isarylalkyl, aryl or heteroaryl optionally substituted with up to 3 groupsselected from the group consisting of halogen, trifluoromethyl, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms orstraight or branched chain lower alkoxy having 1-6 carbon atoms;R₂ ishydrogen, straight or branched chain lower alkyl having 1-6 carbon atomsor phenyl; and R₃ is hydrogen or straight or branched chain lower alkylhaving 1-6 carbon atoms.